Amino-acylamino-acylamino-penicillanic acids



3,268,519 AMEND-ACYLAMINO-ACYLAMINO- PENIOILLANIC ACIDS Harvey E. Alburn, West Chester, and Norman H. Grant,

Wynnewood, Pa., assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Apr. 7, 1964, Ser. No. 358,096 4 Claims. (Cl. 260239.1)

This invention relates to new synthetic penicillins having potent activity against Gram-negative and Gram-positive microorganisms.

In our copending patent application Ser. No. 353,574, filed March 20, 1964, and of which the present application is a continuation-in-part, there is disclosed a novel method for preparing amino-acylamino-acylamino penicillanic derivatives.

With the use of the method described in the said copending application, there has been discovered a series of new penicillanic acid derivatives having the formula:

Where n is 1 to 4; and Y is of the group consisting of:

Where R is of the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkaryl, and substituted alkaryl; and

R is of the group consisting of alkyl and aryl;

NH: where 11:2 to 9; (3) 1112 1'11 l R HNR where R R R and R are of the group consisting of hydrogen, alkyl, nitro, sulfo, amino, halo and hydroxy;

R and R R and R and R and. R when respectively joined, complete a ring of the group consisting of aryl and alicyclic; and

R is of the group consisting of hydrogen and lower alkyl;

where R R R and R are of the group consisting of hydrogen, alkyl, hydroxy, alkoxy, halo, amino and nitro;

United States Patent 0 ice where Where R is of the group consisting of hydroxy and alkyl, and 11:2 to 7; and

b ll'Iz Where 11:1 to 4.

The new compounds of the series defined above show desirable broad spectrum antibacterial activity and are useful as therapeutic agents in poultry and mammals, including man, in the treatment of infectious diseases caused ,by Gram-positive and Gramnegative bacteria, upon either parenteral or oral administration. They also have use as nutritional supplements in animal feed.

The general process for preparing the aforesaid novel amino-acylamino-acylamino-penicillanic acids is described and claimed in said copending application and comprises generally the reaction of a '4-substituted-2,5-oxazolidinedione (also known as an N-carboxy-amino acid. anhydride) with a 6-(arnino-acylamino)-penicillanic acid under controlled conditions. Methods for the preparation of the N-carboxy amino acid anhydride and 6-(aminoacylamino)-penicillanic acid reactants suitable for use in the process are also described in or referred to in said copending application.

In a preferred method for preparing the amino-acylamino-acylamino-penicillanic acids of the present invention, the 4-substituted-2,S-oxazolidinedione chosen is reacted with the selected 6-(tx-amino-acylamino)-penicillanic acid in approximately equimolar quantities in a cold aqueous solution in a pH range from about 3.8 to about 7.4 and preferably in the range 4.7-7.0. The mixture is stirred for several hours at a temperature from just above the freezing point of the aqueous mixture to about 37 C., and preferably in the range Ol0 C. Although not essential, it may "be preferred to include a buffer having an ionic strength of about 0.02, preferably about 0.3, to aid in keeping the reaction mixture within the required pH range. Suitable buffers for maintaining the desired pH may be any mixture of Organic or inorganic water-soluble acids, bases, or salts such as sodium acetate-acetic acid, calcium acetate-acetic acid, pyridine-acetic acid, formic acid-ammonia, etc. Alternatively, the reaction mixture may be maintained Within the requisite pH range by careful addition of a base such as NaOH or the like.

The following examples are illustrative of the inven tion, but are not to be considered necessarily limitative thereof.

3,268,519 3 4 EXAMPLE I the penicillin compounds with an amine or diamine base,

e.g., procaine, or various N,N'-disubstituted alkylenedi- 6 [DL (o'ammolieilzcmildolglum]amamldo] amines, such as N,N-dibenzylethylenediarnine, etc.

pemczllamc LZCld We claim: Mix 275 g. (0.8 millimoles) of 6-(DL-a-aminoglu- 1. Acornpound of the formula: taran1amido)penicillanic acid with 130 mg. (0.8 rnillimoles) of isatoic anhydride in 20 ml. of ice-cold water. Stir at 12 for 60 minutes, keeping the pH at 6.0 by the addition of 1 N NaOH. Filter, and freeze-dry the filtrate. The product is active against Staph. am'eus and E. coli.

EXAMPLE II 6 [DL-oc- (2-amin0-5-nizr0benzamido)glurm'amamido] perzicillmzic acid Mix 290 mg. (0.8 millimoles) of 6-(DL-a-aminoglutaramamido)penicillanic acid with 165 mg. (0.8 millimoles) of 6-nitroisatoic anhydride in 20 ml. of ice-cold water. Stir at 1-2 for 60 minutes, keeping the pH at 6.0 by the addition of l N NaOH. Filter, and freeze-dry the filtrate. The product is active against Staph. aureus and E. coli.

EXAMPLE III When in the procedure of Example II, the N-carboxyanhydride of S-nitroanthranilic acid is replaced by 0.8 millimoles of the N-carboxyanhydride of (l) 1-aminocyclopropanecarboxylic acid (2) 1-aminocyclodecanecarboxylic acid (3) 2-arnino-3-naphthoic acid (4) Z-methylamino-S-nitrobenzoic acid (5) L-a-aminO-S-methylindole-3-propionic acid (6) L-a-amino-5-ethylindole-3-propionic acid (7) L-wamino-5-methoxyindo1e-3-propionic acid (8) D-2-amino-3-(ethylthio)-propionic acid (9) DL-2-amino-3-(rnethylthio)-propionic acid (10) DL-2-arnino-7-(methylthio)-heptanoic acid (1 1) D-ethionine (12) DL-Z-ethylamino2-pheny1glycine 13) DL-Z-lamylamino-2-phenylglycine (14) 2-carboxytrimethyleneimine (15) Z-carboxyoctamethyleneimine the corresponding penicillin derivatives, all active against Gram-positive and Gram-negative microorganisms, are produced.

EXAMPLE IV When in the procedure of Example II, the 6-nitroisatoic anhydride is replaced by 0.8 millimoles of the N-carboxyanhydride of (1) D-phenylglycine (2) D-phenylalanine (3) L-phenylalanine (4) l-aminocyclopentane carboxylic acid (5) 2-amino-5-nitrohenzoic acid (6) D-tryptophon (7) L-tryptophan (8) DL-phenylsarcosine (9) N-phenylglycine 10) L-proline 1 1) DL o-ethoxyphenylglycine 12) L-cystine (13) glycine (14) Z-amino-S-chlorobenzoic acid (15 Z-amino-S-rnethylbenzoic acid the corresponding penicillin derivatives, all \active against Gram-positive and Gram-negative microorganisms, are produced.

As will be understood by those skilled in the art, the compounds of the invention may be utilized in their acid form or in the form of the therapeutically-active salts thereof, e.g., the sodium or potassium salts, or hydrochloride, etc., or in the form of the pharmaceutioally-acceptable acid-addition salts prepared by the reaction of where n is 1 to 4; and Y is of the group consisting of:

(C H2)n C-C O- where 11:2 to 9;

R4 HNR5 wherein R R R and R are of the group consisting of hydrogen, alkyl, sulfo, nitro and c-hloro; R and R when joined complete a naphthylene ring; and R is of the group consisting of hydrogen and lower alkyl;

where R R R and R are of the group consisting of hydrogen, lower alkyl and lower alk- Y;

( RS(C H2) 11-? H-G 0 where 11:1 to 5, and R is of the group consisting of hydrogen and lower alkyl;

5 Q Where 3. 6-[DL 0c (2 amino 5 nitr0benzamid0)g1utar- R is of the group consisting of hydroxy and amid01penici11anic acid.

alkyl, 4. 6'[DL-a (D 2 amino 2 pheny1aceta1nid0)g1un=2 to 7; and taramidoJpenicillanic acid. (7) H NC O(CH2).1CHC 0- 5 No references cited.

ALEX MAZEL, Primary Examiner. where 11:1 to 2.

2. 6 [DL-o-(o-aminobenzamido)g1utaran1ido1penici1- HENRY JILES Examiner l anic acid. 10 JAMES W. ADAMS, JR., Assistant Examiner. 

1. A COMPOUND OF THE FORMULA: 